There has been a long-standing interest in gaining further insights into rare tumors whose etiology is poorly understood. At present, this project is focusing the majority of efforts on four tumors--nasopharyngeal cancer, biliary cancer and liver cancer.<BR;BR>Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer, other factors, both genetic and exogenous, are also thought to be important. To investigate genetic, dietary, occupational, and behavioral factors related to the etiology of NPC, two studies were conducted in Taiwan - a case-control study of approximately 1,000 individuals and a multiplex family study of approximately 3,000 individuals (350 families). To date, our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes, specific patterns of HLA and KIR genes, and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk;in contrast, formaldehyde exposure was not a significant risk factor. Exogenous risk factors identified within our family study were similar to those observed from our case-control study. Evaluation of gene expression profiles from nasopharynx tumor and normal cells suggest that genes involved in DNA repair and in the metabolism of nitrosamines are involved in NPC pathogenesis. Results from our tissue-based expression studies also suggest the possibility of loss-of-heterozygosity on the telomeric end of chromosome 14 in NPC, and that EBV gene expression within NPC tumor cells affect the expression of host genes involved in immune presentation. This suggests a possible mechanism by which EBV manages to evade immune surrveillance in NPC. Uaffected individuals from multiplex NPC families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To evaluate the possibility that these individuals with elevated levels of antibodies against EBV are at increased risk of NPC clinical follow-up of this population is underway. A genome-wide screen is also underway to permit an evaluation of chromosomal regions linked to NPC development within our families.<BR;BR>Biliary tract cancers are relatively rare but fatal malignancies. During the last 25 years, the incidence of biliary tract cancer in Shanghai has increased more rapidly than that of any other malignancy. The sharply rising trend suggests a change in the prevalence of risk factor or interaction between these factors and genetic susceptibility. To elucidate these factors, we conducted a population-based interdisciplinary study of biliary tract cancer. More than 3,000 subjects were enrolled in the study, including over 600 biliary tract cancer patients, 900 gallstone patients, and 1,000 healthy controls randomly selected from the population. A structured questionnaire was used to elicit information on epidemiologic risk factors, including smoking, drinking, diet, medical history, and reproductive factors. The study had a strong biochemical and molecular component with an extensive collection of biological samples, including serum, DNA, gallstones, bile, and tissue samples. Molecular data from this population-based study show that these three subistes have distinct molecular changes, including mutations of beta-catenin, p53, p16, and K-ras. Interview data suggest that excess risks of biliary tract cancer were associated with a history of gallstones, a history of chronic hepatitis or liver cirrhosis, a family history of gallstones, parity (for gallbladder cancer, among women only), obesity, consumption of preserved foods, and a history of cholecystitis or pancreatitis. In contrast, tea drinking and aspirin use were associated with reduced risk, especially among women. Chronic carriers of the hepatitis B virus had a 2-fold risk of bile duct cancer and diabetes was associated with a 2-fold risk of gallbladder stones and gallbladder cancer. A number of variants of genes in the lipid metabolism, hormone metabolism, inflammation, and DNA repair pathways, including variants of the estrogen receptor gene (ER-alpha), CYP17, apolipoprotein E (APOE), apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), PTGS2, TNF, Inerleukin 8 (IL8), IL8R, AR CAG repeats, and DNA repair genes (XRCC3 and MGMT84), were associated with an increased risk of biliary tract cancer, in particular bile duct cancer.<BR;BR>Primary liver cancer, composed of two major histologic types, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the sixth most frequently occurring cancer in the world and the third most common cause of cancer mortality. Over 80% of liver cancers occur in Asia and sub-Saharan Africa, though incidence in low-rate areas, such as the U.S. and Europe, has been rising. While hepatitis B virus and aflatoxin consumption are major risk factors for HCC in high-rate areas, not all exposed persons develop HCC. In an effort to identify other risk factors for HCC, we are currently examining associations with organochlorine pesticides and fumonisin B1 in an HCC endemic area of China. In the U.S., our research has focused on identifying factors associated with the increase in incidence of both HCC and ICC. In record-linkage studies, we have found that hepatitis B virus, hepatitis C virus and diabetes are linked to the increasing incidence of HCC, while hepatitis C virus, human immunodeficiency virus, cirrhosis and diabetes are linked to the increasing incidence of ICC. To follow-up on these finding, we are currently examining the relationship of metabolic syndrome to risk of both types of liver cancer.<BR;BR>We have recently extended our interests in the etiology of breast cancer to also include a focus on rarely occurring male breast cancers. In an analysis within the large NIH-AARP cohort study, we identified that a family history of breast cancer in a female relative, obesity, physical inactivity and a history of bone fractures related to increased risk. An investigation within the U.S. Veterans Affairs computerized medical care system database found increased risks of male breast cancer associated with hospitalizations for Klinefelter syndrome, obesity, diabetes, gynecomastia, orchitis/epididymitis and cholelithiasis (latter only among African Americans). We are currently following up these findings in a pooled analysis in which we hope to include data from the majority of case-control and cohort investigations. Cohort investigations will be particularly valuable towards assessing relationships with genetic markers and endogenous hormones.<BR;BR>Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at a risk of anal cancer that approaches the risk of cervical cancer for unscreened women living in developing countries. There is currently no accepted method for screening HIV-positive MSM for anal precancer to reduce the morbidity and mortality due to anal cancer;in the absence of a standard and effective screening modality, clinics often resort to anoscopy, a diagnostic procedure akin to colposcopy, and directed biopsies on all HIV-positive MSM. At Kaiser Permanente Northern California, we are enrolling 1,000 HIV-positive MSM in a 2-year study to describe the natural history of HPV and evaluate the clinical utility of various tests to detect prevalent, 1-year cumulative, and 2-year cumulative anal precancer and cancer.